(a) Field of the Invention
The invention relates to novel inhibitors of pyruvate kinase and ATP production specific for the treatment of cancer, pharmaceutical compositions and methods of treatment of cancer thereof.
(b) Description of Prior Art
Most malignant tumors have much higher glucose uptake and glycolysis rates than noncancerous tissues. This is characteristic for many human tumors (including those of brain, liver, lung, colon, stomach and breast). The higher metabolism of glucose is needed by the tumor cells for ATP production, via the glycolysis pathway resulting in pyruvate and ATP:Glucose+2NAD++2ADP+2Pi→2pyruvate+2NADH+2H++2ATP+2H2O
The regulation in the rate of glycolysis is usually achieved by two glycolytic enzymes, one of which is pyruvate kinase (PK). The pyruvate kinase catalyzes the conversion of phosphoenol pyruvate (PEP) to pyruvate with the coupled transfer of the phosphoryl group from PEP to ADP giving ATP:

Several isoforms of pyruvate kinase are known in a tissue-specific manner, such as. L-PK in liver and kidney and M1-PK in brain and muscle. During multi-step carcinogenesis, there is the loss of the tissue-specific isoforms of PK, followed by the expression of the tumor M2-PK (E. Eigenbrodt et al., Crti. Reve. Oncog. 3 (1992) 91-115.). Recently the use of the detection of tumor M2-PK as a marker for cancer monitoring, including renal cell carcinoma, gastrointestinal cancer (J. Schneider, G. Schulze, Anticancer Research, 23 (2003) 5089-5093), breast cancer (S. Yilmaz, S. Ozan, I. H. Ozercan, Arch Med Res 34 (2003) 315-324) and lung cancer (J. Schneider et al., Cancer Letters, 193 (2003) 91-98) has been advocated.
Inhibition of ATP production is a plausible strategy for the treatment of cancer. Recently, the use of 3-bromopyruvic acid (3-BrPA) in a direct intraarterial injection to suppress implanted rabbit liver tumors has been reported (J.-F. H. Geschwind et al., Cancer Research, 62 (2002) 3909-3913; US patent application published under No. US 2003/0087961 on May 8, 2003). The inhibition of ATP production via inhibition of hexokinase using 3-bromopyruvic acid (3-BrPA) has been suggested (Y. H. Ko et al., Cancer Letters, 173 (2001) 83-91), however there is a need for novel inhibitors of ATP production which are more stable and efficacious.
It would be highly desirable to be provided with novel inhibitors of pyruvate kinase and ATP production specific for the treatment of cancer.